Mitochondrial plasticity promotes resistance to sorafenib and vulnerability to STAT3 inhibition in human hepatocellular carcinoma
Informazioni aggiuntive
Autori
Pandit S. K.,
Sandrini G.,
Merulla J.,
Nobili V.,
Wang X.,
Zangari A.,
Rinaldi A.,
Shinde D.,
Carbone G.,
Catapano C.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2021
Lingua
Inglese
Sommario
The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stagehepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innateand acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt tocontinuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profoundreprogramming of mitochondria function and marked activation of genes required for mitochondrialprotein translation and biogenesis. Mitochondrial ribosomal proteins and components of translationand import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patientsshow similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated(pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionabletarget to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727,reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. Theseresults sustain the importance of mitochondria plasticity in response to sorafenib and identify aclinically actionable strategy for improving the treatment efficacy in HCC patients.
Parole chiave
Liver cancer, Hepatocellular carcinoma, Sorafenib, Tyrosine kinase inhibitors, Drug resistance, Mitochondria, Mitochondrial protein translation, Mitochondrial ribosomal proteins, STAT3, OPB-111077
Periodico
Cancers
Volume
13
Numero ( Mese )
23
Pagine (o numero dell’articolo)
6029
Diffusione
Licenza
CC BY
Visibilità
Pubblico
Status open access
Gold
